Abstract Recent data suggest that Alzheimer?s disease (AD) and type 2 diabetes (DM) share biologic pathways. Non- esterified fatty acids (NEFAs) play a central role in the pathogenesis of DM via impaired insulin signaling in skeletal muscle, resulting in insulin resistance, and inhibition of glucose transport and key enzymes of glucose metabolism. Concomitantly, NEFAs impair ?-cell insulin secretion and stimulate hepatic gluconeogenesis. Previous studies confirmed that NEFAs can cross the blood-brain barrier, making them highly plausible candidates to link DM with AD. Our recent work in the Cardiovascular Health Study (CHS) extends the NEFA- AD link to human populations for the first time. In this ongoing cohort study of 5,888 older adults, we have found that circulating NEFA levels are associated with 1) dementia-specific mortality, 2) adjudicated incident dementia, 3) longitudinal cognitive decline, and 4) incident frailty, even after extensive adjustment for other cognitive risk factors. With funding from NIA (R01-AG053325), we are now studying the relationship of individual NEFAs, post-load NEFAs, and change in NEFAs over time with cardiometabolic risk in CHS. Because CHS will soon have two longitudinal measures of total NEFAs along with repeated cognitive assessments, routine cranial MRI, and stored specimens with which to measure dementia-related biomarkers, such as circulating beta amyloid or YKL40, it is uniquely well-suited to characterize the role that NEFAs may play in AD and concurrent cognitive loss. The current supplement will examine the associations of individual NEFAs and NEFA patterns, post-load NEFAs, and change in NEFAs over time with incidence of dementia, brain atrophy, and plasma levels of beta-amyloid peptide 1-42 and YKL40 in older adults. This project leverages CHS? unique data and specimen resources, a well-phenotyped cohort and a research team with a proven track record of collaborative success, and ongoing NIA-funded project to tackle the central role of NEFAs in dementia. Our proposed aims are directly responsive to NOT-AG-18-008, which seeks ?to expand existing awards?that are not currently focused on Alzheimer?s disease (AD) and its related dementias (ADRD) to allow them to develop a focus on AD/ADRD.?